1. Field of the Invention
This invention relates to methods and compositions for efficiently delivering iron to a patient. More particularly, the present invention is concerned with dialysates and dialysate concentrates, and methods for delivering to a patient via dialysis a composition comprising ionic iron complexed with one or more anions. An iron complex selected according to the invention is non-polymeric; soluble in an aqueous medium; chemically stable, thereby preventing the dissociation of iron ions from the anions under conditions according to the invention; and can be well absorbed by blood and the living body.
2. Description of Related Art
Iron is a metal which is an essential requirement for tissue growth in humans and many animals. Therefore, an adequate supply of iron is critical to their survival and well-being. Although there is normally an ample amount of iron in the diet, the level of absorption of iron from food is generally low and, therefore, the supply of iron to the body can easily become critical under a variety of conditions. For example, iron is a necessary ingredient in the production of red blood cells, and a lack of iron may quickly lead to anemia. Iron deficiency anemia is commonly encountered, for example, in pregnancy and may also present a problem in the newly born. Moreover, in certain pathological conditions there is a maldistribution of body iron leading to a state of chronic anemia. This is seen in chronic diseases such as rheumatoid arthritis, certain haemolytic diseases and cancer.
Anemia is also uniformly present in patients with end stage renal disease (ESRD). The major cause of this anemia is the deficient production of erythropoeietin hormone (EPO) by the native kidneys. EPO stimulates the bone marrow to produce red cells, and when EPO is deficient, patients invariably become anemic. To counter the anemia of ESRD patients, recombinant EPO (which is very expensive) may be administered subcutaneously or intravenously. Recombinant EPO can effectively increase the hematocrit of patients with adequate iron stores, but the increased rate of production of new red cells quickly depletes body iron stores and, when this occurs, EPO becomes completely ineffective. As such, the delivery of iron to an ESRD patient is critical to his or her treatment. Methods in the prior art for delivering iron to a patient, such as an ESRD patient, have proven largely impractical and unsatisfactory, and there is a great need for improved methods of iron delivery.
It is well known that iron is very difficult to assimilate into the cells of a living organism and when an iron deficiency exists, oral iron supplements in relatively large doses are commonly administered wherein the iron may be in a wide variety of forms, i.e., usually as various organic and inorganic salts. Iron compositions which have been previously administered orally include, for example, ferrous gluconate, ferrous citrate, ferrous sulfate, ferrous fumarate and ferric-polysaccharide complexes. As a specific example of a condition where oral iron delivery is common, ESRD patients are typically directed to take oral iron tablets when EPO is started, as discussed above.
Oral iron administration, however, has several disadvantages. Patient noncompliance, gastrointestinal side effects, interactions with other oral medications and very poor absorption in ESRD patients markedly limit its effectiveness. For example, patients often stop taking these medications because of side effects associated therewith, such as constipation and gastric irritation. Additionally, these oral iron preparations cause a patient's stools to turn black, thereby making it difficult for caregivers to detect gastrointestinal bleeding during iron therapy. It is believed that these problems are all related to the administration of relatively high dosage levels of oral compounds due to the low level of iron uptake by the body, and these high doses are thought to also cause siderosis of the gut wall.
To overcome the above-described problems with oral delivery of iron, a great deal of effort has been directed to developing iron delivery methods wherein iron-containing compositions are delivered parenterally, either by intravenous or intramuscular injection. In this regard, it is currently widely believed that compositions used for non-oral iron administration must be in macromolecular form. This mindset is based upon the belief that the use of macromolecules eliminates the problem of osmolarity in the case of intramuscular injection, and, in the case of intravenous injection, the belief that macromolecular compositions are required to ensure that free iron is not introduced into the blood. Since iron is slowly freed from such macromolecules by the action of metabolism, and then bound by transferrin in the blood as it slowly becomes available, administration of iron in macromolecular forms is presently thought to be the only viable option with respect to intravenous administration techniques.
With respect to intravenous administration, iron-dextran (INFED®), which may be obtained from Schein Pharmaceuticals, Phoenix, Ariz., is commonly administered intravenously to ESRD patients to increase iron stores, with about 100-200 mg injected each successive dialysis until about 1000 mg are administered. Iron dextran is a macromolecule having a high average molecular weight ranging generally between about 100,000 and about 200,000. However, iron dextran occasionally causes severe allergic reactions, fever and rashes during injection and must therefore be administered slowly and after a small test dose. Ferric gluconate is another macromolecular iron complex for intravenous administration, and is relatively free of symptoms. However, each of these intravenous iron preparations is very expensive and requires a great deal of time and skill for administration. The large expense related to these intravenous preparations is associated in part with the necessity for sterilization of the injectant. Additionally, intravenous administration requires venous access, which is available during hemodialysis, but not commonly available in peritoneal dialysis patients. Finally, only about half of iron in iron dextran is bio-available after intravenous injection for red cell production. The fate of the rest is unknown.
With respect to intramuscular injection, iron dextrins and iron dextrans may be administered intramuscularly; however, as a result of their high molecular weights, absorption in the human or animal body is incomplete. Furthermore, the administration of these compositions intramuscularly is painful and often results in an undesirable discoloration at the injection site. Alternatively, U.S. Pat. No. 3,686,397 to Muller teaches an iron preparation for intramuscular-injection which comprises a nonionic complex of trivalent iron supplied a ferric hydroxide with a complex forming agent consisting of sorbitol, gluconic acid and certain oligosaccharides (polyglucoses) in certain proportions and amounts. Other. macromolecular iron preparations which may be administered via intramuscular injection are taught in U.S. Pat. No. 5,177,068 to Callingham et al., U.S. Pat. No. 5,063,205 to Peters et al., U.S. Pat. No. 4,834,983 to Hider et al. and U.S. Pat. No. 4,167,564 to Jenson. Many preparations, such as that taught in the Jenson patent, may be administered parenterally either by intramuscular or intravenous injection.
Recently, it has been proposed that iron may be administered to a mammal by intraperitoneal delivery of macromolecular iron dextran. It has been found that only about half of the iron delivered intraperitoneally in this form is bioavailable, passing to the blood and then to the reticulo-endothelial system and bone marrow, where it is incorporated into red cells. It appears that about 50% of the iron dextran is stored permanently in the body and is not avaialable for red cell production. There is evidence that macrophages near the peritoneum pick up iron-dextran and store it within themselves, creating an abnormal physical condition which could lead to abnormal membrane changes in the peritoneum.
In light of this background, there is a great need in the art for improved methods for delivering iron to a patient. The present invention addresses the problems in the prior art by providing methods and compositions for delivering iron by transfer of a low molecular weight (non-polymeric) iron complex from dialysate. Inventive methods are surprisingly effective in light of conventional thought, which teaches that complexes selected according to the invention do not have sufficient solubility to be useful in this manner. Further, it is widely believed that soluble iron complexes are unacceptable iron delivery agents, this belief being based upon a fear of the toxicity of free iron in blood.
The present inventor has discovered that iron complex compositions selected in accordance with the invention are tightly complexed and are highly soluble, and can thereby be safely administered to a patient using dialysis with minimal staff effort and very little risk. This high solubility also advantageously allows an inventive complex to be included in dialysate concentrates, which are described in greater detail herein. For hemodialysis applications, the iron can be added to a dialysate or a concentrate just as other solutes, in “clean” form and need not be sterilized. For peritoneal applications, the iron composition can be sterilized.